Called a molecular network diverter, this new switch combines existing biological techniques into a meta-tool that can sense and modulate the signals that regulate the molecular machinery of life.

By Tom Abate

A Stanford bioengineering lab has developed a technology that can tweak the control systems that regulate the inner workings of cells, pointing the way toward future medical interventions that could switch off diseased states or turn on healthy processes.

The research paper being published today by Science Express describes a biological tool that principal author Christina Smolke, PhD, associate professor of bioengineering, has dubbed a molecular network diverter.

This molecular diverter utilizes the concerted action of three biological sub-systems to redirect signaling pathways – complex networks of molecular interactions that orchestrate the cellular machinery.

The experiments described by Smolke and her collaborators, Kate Galloway, PhD, California Institute of Technology, and Elisa Franco, PhD, assistant professor of mechanical engineering at University of California, Riverside, were performed on yeast cells.

But the principles and practices embodied in the molecular network diverter apply to signaling pathways that control the development, reproduction and death of all cells. When these signaling pathways go awry in humans, for instance, such malfunctions can cause many types of cancer as well as other diseases.

“We’re doing this in yeast, but there’s a lot of conservation (similarity) of these pathways in higher organisms,” Smolke said. “The next step, now that we’ve shown this in simpler systems, is to take this technology into human cell cultures.”

The Stanford team’s initial goal was to control the mating behavior of yeast, an activity that, in nature, is influenced by the presence or absence of pheromones.

In a series of experiments, Smolke and her collaborators tried various techniques to induce or inhibit yeast mating behavior irrespective of pheromone activity.

At first they found that the various techniques they used canceled each other out. But through computational modeling and fine-tuning of the chemical components they were able to build the molecular network diverter by joining three techniques into a unified technology whose elements they call:

The transducer, which is an RNA-based system that gathers information about the chemical environment of the cell;

The promoter, the molecular agent that helps to initiate and modulate the desired change; and

The pathway regulator, which finds the appropriate point in the cell’s signaling pathway to make the intervention.

“The pieces that we used to build this control system existed,” Smolke said. “Combining them in a modular fashion into this molecular network diverter is what’s new.”

By chemically tuning this molecular network diverter in different ways, the Stanford lab was able to: induce yeast to mate in the absence of pheromones; inhibit mating behavior even when pheromones were present; and engineer cell lines that contained this pathway-regulating mechanism in a neutral state until and unless researchers flipped this chemical switch.

“We’ve created this tool and the tool itself is the control system and the methodology of implementing it,” Smolke said, adding that based on this proof of principle “we’re able to propose other generalized design strategies.”

Her assessment was echoed by James J. Collins, PhD, a professor of biomedical engineering at Boston University and a researcher with the Wyss Institute at Harvard University.

Christina D. Smolke, associate professor of bioengineering, and her collaborators have developed a technology that can tweak the control systems that regulate the inner workings of cells. (Linda A. Cicero)

Collins, who was not associated with the experiment, said Smolke and her team had demonstrated a new, systems-approach toward building tools for bioengineering.

“It shows that we don’t need to start from scratch. We can achieve advances by harnessing components that we already have,” said Collins, who termed the work “an application of engineering principles to cell biology” and “an important advance for synthetic biology.”

Tom Abate is associate director of communications in the School of Engineering.